The major limitation to the sustainable suppression of HIV-1 infection is the emergence of drug-resistant mutants during the course of therapy. The emergence of resistant variants in response to drug selection is attributed to the extensive genomic variability of HIV-1. The overall purpose of this research is to understand the fundamental mechanisms of HIV-1 mutation. We are specifically interested in determining the alterations in the molecular mechanisms of mutation associated with the acquisition of drug resistance. The specific aims are: 1) to isolate novel drug-resistant mutants of HIV-1 reverse transcriptase with altered fidelity of DNA synthesis; 2) to compare the fidelities of wild-type and drug-resistant mutator RTs; and 3) to assess the contribution of changes in RT fidelity to changes in the overall mutation rate of HIV-1. Strategies for the treatment of HIV-1 infection must take into account the high genetic variability of the virus and any perturbations to the rate of variation resulting from therapeutic pressure. The proposed studies should provide valuable insights into the basic mechanisms of HIV-1 mutation and guide the development of more effective therapeutic strategies to control HIV-I infection.